IGFBP3 As a Potential Biomarker and Therapeutic Target in Hepatocellular Carcinoma: A Multi‐Cohort Analysis

OBJECTIVE: This study aimed to investigate the expression patterns and prognostic significance of insulin-like growth factor-binding protein 3 (IGFBP3) in hepatocellular carcinoma (HCC) and other cancer types. METHODS: IGFBP3 expression was analyzed using The Cancer Genome Atlas (TCGA)-LIHC, International Cancer Genome Consortium (ICGC-LIRI-JP), Gene Expression Omnibus (GEO; GSE102079 and GSE112790), and Genotype-Tissue Expression (GTEx) databases. Experimental validation included immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR) on 10 paired HCC tissues. Survival was assessed via Kaplan-Meier analysis in TCGA, ICGC, and 47-patient cohorts stratified by IGFBP3 immunoreactive score (IRS). Univariate and multivariate Cox regression identified prognostic factors. Immune infiltration correlations were evaluated using ESTIMATE and TIMER algorithms, with pan-cancer analysis conducted via TCGA database. RESULTS: IGFBP3 was significantly downregulated in HCC across all cohorts and validated in our cohort (p < 0.01). Elevated intratumoral IGFBP3 correlated with advanced tumor stage, high grade, and elevated AFP. High IGFBP3 predicted poorer overall survival in TCGA (HR = 1.666, p = 0.004) and ICGC (HR = 4.631, p = 0.0009), and was associated with shorter survival in our cohort (p = 0.0002). Multivariate analysis confirmed IGFBP3 as an independent prognostic factor (HR = 2.95, p = 0.014). IGFBP3 expression positively correlated with immunosuppressive cell infiltration (M2 macrophages, regulatory T cells) and enriched pathways including TGF-β and JAK-STAT signaling. Pan-cancer analysis revealed cancer-specific expression patterns, with HCC showing both overall downregulation and high-risk prognostic value in high-expression tumors. CONCLUSION: IGFBP3 was low expression in HCC, yet high expression indicates poor prognosis. This suggests that IGFBP3 is a potential novel prognostic biomarker and therapeutic target in HCC.